P26 Reevaluation of the Critical Flicker Frequency in Patients With Liver Cirrhosis Reveals New Perspectives of Its Diagnostic Impact in the Detection of Hepatic Encephalopathy

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Introduction: The assessment of the critical flicker frequency (CFF) is a widely-used diagnostic tool for the detection of minimal hepatic encephalopathy (mHE) in patients with liver cirrhosis. For CFF assessment patients must repeatedly mark a fusion threshold for light pulses presented by the HEPAtonorm™-Analyzer with decreasing frequency. CFF is calculated as mean of 8 runs. If the standard deviation (SD) of the mean CFF is above 1 in these runs, as many runs are added as needed to achieve 8 runs with a SD below 1. In our experience this applies especially to patients with cognitive alterations. Thus, we aimed to investigate the use of CFF variation as diagnostic tool for mHE. Methods: Overall, 228 patients with liver cirrhosis where included into this study. Clinical characteristics, demographic data and laboratory findings were recorded. Patients underwent PSE-Syndrome test (leading to PHES), inhibitory control test (ICT), continuous reaction time test (CRT) and CFF assessment. PHES <-4, ICT weighted lures >24, CRT Index <1.9 and CFF <39 Hz were rated abnormal. Additionally, age adjusted norms for CFF were applied, and the total number of CFF runs required to achieve a SD <1 as well as the uncorrected standard deviation of the first 8 CFF attempts were registered. Results: Neither CFF <39, nor the age corrected CFF correlated with abnormal PHES results (Table 1). Instead, the number of attempts needed to achieve a SD <1 for CFF and the SD of the first 8 uncorrected CFF attempts were strongly associated with pathological PHES. The number of additional attempts for CFF assessments was also associated with abnormal CRT (P=0.017) and ICT (P=0.027) but did not correlate with MELD or Child Pugh Score. Multiple linear regression analysis, including age, significant comorbidities, concomitant medication, laboratory parameters and PHES results indicated PHES results the only cofactor with independent impact upon CFF variability (B= -0.052; 95% CI= -0.084 - -0.019, P=0.002). Conclusion: The necessity of additional runs for CFF assessment indicates cognitive dysfunction and gives -rather than CFF results- a worthwhile hint for the presence of mHE in patients with liver cirrhosis (see Figure 1). Table 1. - Baseline characteristics of the study cohort with differences in patients with normal and pathological PHES score. Quantities are stated with numbers and percentages. Continuous variables are given as median with interquartile range (IQR). Categorical variables were tested with Chi-square test, for group comparisons Mann-Whitney U test was used, a level <0.05 was considered statistically significant and marked in bold Entire cohort Normal PHES Pathological PHES P-value Number of patients N=228 N=131 (57.5%) N=97 (42.5%) Age in years 57 (50-64) 56 (49-63) 58 (54-66) 0.017 Sex female 67 (29.4%) 41 (31.3%) 26 (26.8%) 0.401 Etiology (multiple selection possible) 0.335 Alcohol related 98 (43%) 51 (38.9%) 47 (48.5%) Alcohol plus other 24 (10.5%) 14 (10.7%) 10 (10.3%) Etiology 106 (46.5%) 66 (50.4%) 40 (41.2%) Non Alcohol related TIPS 46 (20.2%) 27 (20.6%) 19 (19.6%) 0.849 Diabetes 59 (25.9%) 27 (20.6%) 32 (33%) 0.035 Previous oHE episodes 76 (33.3%) 35 (26.7%) 41 (42.3%) 0.014 Years of school education 10 (9-11) 10 (9-11) 10 (9-10) 0.028 PHES -4 (-2 - -7) -2 (-3 – 0) -8 (-6 - -11) <0.001 ICT weighted lures (=Lures/Target Accuracy2) 19.4 (10.5-34) 14 (7.5-24.7) 33.5 (18.5-44.5) <0.001 ICT abnormal 103 (46.6%) 38 (29.7%) 65 (69.9%) <0.001 CRT 1.84 (1.4-2.3) 2.04-1.56-2.46) 1.6 (1.27-2.05) <0.001 CRT abnormal 122 (53.7%) 58 (44.6%) 64 (66%) 0.001 CFF with SD <1 42.5 (38.7-48) 42 (38.7-46.8) 40.7 (36.5-46.1) 0.175 Number of additional CFF attempts needed for SD <1 1 ( 0-4.75) 0 (0-3) 3 (0-7) <0.001 CFF of first 8 attempts (Hz) 42 (38.38-46) 42.2 (38.7-46.65) 41.4 (36.6-45.4) 0.086 SD of first 8 CFF attempts 1.1 (0.8-1.9) 0.9 (0.7-1.6) 1.4 (0.9-2.6) <0.001 CFF abnormal (<39Hz) 69 (31.4%) 34 (27%) 35 (37.2%) 0.105 CFF abnormal (age corrected) 54 (24.7%) 26 (20.6%) 28 (30.1%) 0.108 Sodium (mmol/l) 136 (134-139) 137 (135-139) 136 (132-138) 0.003 Creatinine (µmol/l) 87 (71-111.5) 84 (70-105) 93 (78.5-133.5) 0.006 CHE (kU/l) (3.05 (1.95-4.37) 3.2 (2.3-4.8) 2.7 (1.7-3.9) 0.014 Bilirubin (µmol/l) 27 (15-54) 24 (15-52) 31 (16-60.5) 0.189 Alcalic phosphatase 131 (99.25-186) 126 (95-180) 138 (102-192) 0.408 Albumin (g/l) 33 (28-37) 33 (27.5-38.0) 32 (28-35) 0.267 White blood cells (tsd/µl) 4.9 (3.9-7.0) 4.9 (3.4-6.7) 5.1 (4-7.4) 0.239 Platelets (tsd/µl) 94 (61-142) 100.5 (60.75-150.25) 92 (61.5- 131.5) 0.558 Hemoglobin (g/dl) 10.9 (9.4-13.1) 11.3 (9.6-13.4) 10.5 (8.9-12.65 0.011 INR 1.27 (1.13-1.42) 1.26 (1.1 – 1.38) 1.28 (1.17-1.57) 0.050 Child-Pugh-Score 7 (6-9) 7 (5-9) 8 (6.25-9.75) <0.001 MELD 12.32 (9.36-16.8) 12 (9.1-15.1) 12.7 (9.56-18.45) 0.020 CLIF C-AD Score 47.7 (42.9-52.8) 46.9 (41.9- 51.8) 49.7 (44.9-55.2) <0.001 Lactulose 121 (53.1%) 53 (40.5%) 68 (70.1%) <0.001 Rifaximine 72 (31.6%) 31 (23.7%) 41 (42.3%) 0.003 L-Ornithine L-Aspartate 38 (16.7%) 12 (9.2%) 26 (26.8%) <0.001 Abbreviations: TIPS: Transjugular intrahepatic portosystemic shunt; ICT: inhibitory control test; CRT: continuous reaction time test; CFF: critical flicker frequency; SD: standard deviation; CHE: cholinesterase; INR: international normalized ratio; MELD: Model for End-Stage Liver Disease; CLIF C-AD: CLIF Consortium Acute Decompensation. Figure 1.: ROC analysis for different diagnostic tools to detect cognitive dysfuction, defined by PHES < -4. Abbreviations: ICT: inhibitory control test; CRT: continuous reaction time test; CFF: critical flicker frequency; SD: standard deviation, AUC: area under the curve.

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